Constrained Peptides with Fine‐Tuned Flexibility Inhibit NF‐Y Transcription Factor Assembly

Jeganathan, Sadasivam; Wendt, Mathias; Kiehstaller, S.; Brancaccio, Diego; Kuepper, Arne; Pospiech, Nicole; Carotenuto, Alfonso; Novellino, Ettore; Hennig, Sven; Grossmann, Tom N.

doi:10.1002/ange.201907901

Cited by 6 publications

(4 citation statements)

References 58 publications

(13 reference statements)

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“…Finally, once positions Ser 6 and Gly 10 were identified as suitable for cyclization, they were further investigated by considering the inversion of positions of Lys and Glu amino acids ( 24 ), and the hydrocarbon ( 25 ) and disulfide ( 26 ) linkers. 51 , 52 …”

Section: Resultsmentioning

confidence: 99%

First-in-Class Cyclic Temporin L Analogue: Design, Synthesis, and Antimicrobial Assessment

et al. 2021

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The pharmacodynamic and pharmacokinetic properties of bioactive peptides can be modulated by introducing conformational constraints such as intramolecular macrocyclizations, which can involve either the backbone and/or side chains. Herein, we aimed at increasing the α-helicity content of temporin L, an isoform of an intriguing class of linear antimicrobial peptides (AMPs), endowed with a wide antimicrobial spectrum, by the employment of diverse side-chain tethering strategies, including lactam, 1,4-substituted [1,2,3]-triazole, hydrocarbon, and disulfide linkers. Our approach resulted in a library of cyclic temporin L analogues that were biologically assessed for their antimicrobial, cytotoxic, and antibiofilm activities, leading to the development of the first-in-class cyclic peptide related to this AMP family. Our results allowed us to expand the knowledge regarding the relationship between the α-helical character of temporin derivatives and their biological activity, paving the way for the development of improved antibiotic cyclic AMP analogues.

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Section: Resultsmentioning

confidence: 99%

First-in-Class Cyclic Temporin L Analogue: Design, Synthesis, and Antimicrobial Assessment

et al. 2021

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“…Given its safety and therapeutic efficacy, these results indicate that NFYAv1 may be a valuable and attractive therapeutic target for TNBC. Recently, inhibitors of NF-Y were identified 57 , 58 . These inhibitors bind to NF-Y and inhibit NF-Y-DNA complex formation, thereby blocking the transcriptional promotion by NF-Y.…”

Section: Discussionmentioning

confidence: 99%

NFYA promotes malignant behavior of triple-negative breast cancer in mice through the regulation of lipid metabolism

et al. 2023

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Two splicing variants exist in NFYA that exhibit high expression in many human tumour types. The balance in their expression correlates with prognosis in breast cancer, but functional differences remain unclear. Here, we demonstrate that NFYAv1, a long-form variant, upregulates the transcription of essential lipogenic enzymes ACACA and FASN to enhance the malignant behavior of triple-negative breast cancer (TNBC). Loss of the NFYAv1-lipogenesis axis strongly suppresses malignant behavior in vitro and in vivo, indicating that the NFYAv1-lipogenesis axis is essential for TNBC malignant behavior and that the axis might be a potential therapeutic target for TNBC. Furthermore, mice deficient in lipogenic enzymes, such as Acly, Acaca, and Fasn, exhibit embryonic lethality; however, Nfyav1-deficient mice exhibited no apparent developmental abnormalities. Our results indicate that the NFYAv1-lipogenesis axis has tumour-promoting effects and that NFYAv1 may be a safe therapeutic target for TNBC.

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“…Stabilized α-helices have also been used to generate peptidomimetic inhibitors derived from the A-subunit of the trimeric transcription factor complex NF-Y. 23 Based on a previously reported crystal structure, 24 a 29-mer peptide of NF-YA was used as the initial NF-YB/C-targeting sequence ( PBM ). We performed a truncation study to identify the central 19-mer interaction motif, which then served as the starting point for peptidomimetic design.…”

Section: Constraining the Conformation Of Peptidesmentioning

confidence: 99%

From Protein Structures to Functional Biomimetics

Grossmann,

Durukan

2024

Synlett

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The development of complex molecular scaffolds with defined folding properties represents a central challenge in chemical research. Proteins are natural scaffolds defined by a hierarchy of structural complexity and have evolved to manifest unique functional characteristics e.g., molecular recognition capabilities that facilitate the binding of target molecules with high affinity and selectivity. Utilizing these features, proteins have been used as a starting point for the design of synthetic foldamers, enhanced biocatalysts as well as bioactive reagents in drug discovery. In this account, we describe the strategies used in our group to stabilize protein folds, ranging from the constraint of bioactive peptide conformations to chemical protein engineering. We discuss the evolution of peptides into peptidomimetics to inhibit protein-protein and protein-nucleic acid interactions, and the selective chemical modification of proteins to enhance their properties for biotechnological applications. The reported peptide- and proteomimetic structures cover a broad range of molecular size and they highlight the importance of structure stabilization for the design of functional biomimetics.

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Constrained Peptides with Fine‐Tuned Flexibility Inhibit NF‐Y Transcription Factor Assembly

Cited by 6 publications

References 58 publications

First-in-Class Cyclic Temporin L Analogue: Design, Synthesis, and Antimicrobial Assessment

First-in-Class Cyclic Temporin L Analogue: Design, Synthesis, and Antimicrobial Assessment

NFYA promotes malignant behavior of triple-negative breast cancer in mice through the regulation of lipid metabolism

From Protein Structures to Functional Biomimetics

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